Int. J. Electrochem. Sci., 14 (2019) 5287 – 5304, doi: 10.20964/2019.06.63

International Journal of

ELECTROCHEMICAL SCIENCE

www.electrochemsci.org

Mini review

Metal-Organic Frameworks-Based Electrochemical Sensors and

Biosensors

Feng Zhao, Ting Sun*, Fengyun Geng, Peiyu Chen and Yanping Gao*

College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang, Henan 455000,

People's Republic of China *E-mail: tingsunhx@aliyun.com; fygu2010@163.com

Received: 9 March 2019 / Accepted: 11 April 2019 / Published: 10 May 2019

Metal–organic frameworks (MOFs) exhibit distinguish properties, including permanent porosity,

abundant structures and tailorable surface chemistry. Recently, MOFs have been widely used in the

electrochemical sensing fields as the electroactive materials or signal labels. This review focuses on

the recent progress in the development of MOFs-based electrochemical sensors and biosensors.

Keywords: Metal-organic frameworks; electrochemical biosensors; signal labels

1. INTRODUCTION

Metal-organic frameworks (MOFs), formed by organic ligand and metal ions or clusters via

strong coordination bonds, are a promising class of crystalline porous materials due to their distinguish

properties, such as permanent porosity, abundant structures and tailorable surface chemistry. MOFs

have offered a wide range of applications in catalysis, energy, separation, gas storage, biomedical

imaging, drug delivery and so forth [1-3]. Recently, numerous research groups have putted increasing

attentions to explore the application of MOFs as sensing materials, including optical, electrochemical,

mechanical, and photoelectrochemical sensors, categorized by signal transduction [4, 5]. Particularly,

the utilization of MOFs as the signal labels of electrochemical sensors is one of their most important

and potential applications. Some of MOFs exhibit good electrochemical activity and cab be employed

to develop novel electrochemical sensors if metal ions and organic linkers of MOFs are well designed.

Meanwhile, MOFs with high specific surface areas and exposed active sites can possess the superior

enzyme-like catalytic activity for a range of substrates, which endows them with the potential to being

used as nanozymes to construct different types of sensors. For example, Cu-based MOFs have been

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reported to have intrinsic peroxidase-like activity for the catalytic oxidation of TMB in the presence of

H2O2 [6]. Although a lot of papers involving in MOFs-based sensors have been published,

electrochemical applications of MOFs as the signal labels are still limited because of their weak

electronic conductivity and electrocatalytic ability.

In view of the rapid development of nanoscience, in the past decades, the developments and

innovations in preparation and assembly of nanomaterials have opened numerous opportunities for

improving the performance of MOFs in electrochemical-related field. Different hybrids have been

synthesized by integrating other functional guest molecules or nanomaterials into MOFs [7]. Among

those preeminent hybrids, the combination of MOFs and carbon nanomaterials, such as carbon

nanotubes (CNTs) and graphene oxide (GO), can dramatically improve the electrical conductivity and

mechanical strength of the nanocomposites. On the other hand, the challenges lay in the low catalytic

activity of MOFs could also be overcome by assembling catalytically active guest materials into

MOFs. For example, metal nanoparticles (NPs) including palladium, gold, copper, and ruthenium have

been used to decorate MOFs for an increased catalytic efficiency.

This review highlights the recent developments in MOFs as electrochemical sensors and

biosensors. First, we briefly summarize the application of some MOFs as the electrochemical materials

for electrocatalysis. Then, we mainly focus on the design of MOFs as the signal labels, in which MOFs

can be used as electrocatalytic labels for signal amplification and as carriers for metal ions and

functional biomolecules (DNA, aptamers, antibody and enzymes).

2. MOFS AS THE ELECTROCHEMCIAL MATERIALS FOR ELECTROCATALYSIS

In general, the metal ions or clusters of inorganic nodes in MOFs can exhibit electrocatalytic

oxidation/reduction ability toward various molecules. The functional groups in organic linkers can

adsorb targets of interest as preconcentration for further electrocatalysis. To date, plenty of molecules

have been efficiently determined by directly using MOFs as electrocatalytic electrode materials,

including hydrogen peroxide, nitrite, metal ions, glucose and other small organic molecules. The

analytical performances are listed in Table 1.

H2O2 detection has attracted worldly attention due to its wide applications in fuel cells,

pharmaceutical industry, food industry, and environmental protection. It is well known that H2O2

undergoes electrochemical oxidation or reduction processes at solid electrodes. Since Cu-MOFs were

used as electrocatalysts for H2O2 oxidation, a few of nonenzymatic electrochemical sensors for H2O2

have been developed and investigated based on different MOFs [8-11]. To improve the electrocatalytic

ability toward H2O2 oxidation or reduction, many nanocomposites, including MOF’s derivates and

hybrids with nanomaterials or proteins, have been prepared and used to detect H2O2 [12-17]. For

example, Xu and co-workers demonstrated that UiO-66 encapsulated with platinum nanoparticles (Pt

NPs) can be used for nonenzymatic detection of H2O2 [14].

Accurate, rapid, and sensitive detection of nitrite (a well-known preserving agent and

biomarker in the food and health industries) have attracted much attention. Zirconium-based porphyrin

MOF (MOF-525) and Pd/NH2-MIL-101(Cr) have been demonstrated to exhibit good electrocatalytic

activity for nitrite oxidation [18, 19]. Moreover, Au microspheres on Cu-MOFs could further decrease

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the oxidation potential by accelerating the electron transfer rate of electro-oxidation of nitrite.

Heavy metal ions have been widely recognized as hazardous factors to environment and

human, and could be detected by anodic stripping voltammetry. Due to the large surface area and

tunable chemical functionality, MOFs and their hybrids can be used to modify the electrode, in which

the composite can adsorb metal ions via the interaction between hydrophilic groups and metal cations

and thus enhance the performance of the electrode [20-23]. Wang and co-workers reported that UiO-

66-NH2 prepared by in situ growth with graphene aerogels (GA) as the backbone can be modified on

the glassy carbon electrode (GCE) for simultaneous detection of multiple heavy-metal ions [23].

In 2013, Mao’s group firstly demonstrated that ZIFs can serve as the matrix for co-

immobilization of methylene green (MG) (a redox active dye) and glucose dehydrogenase (GDH) (a

dehydrogenase) onto the electrode surface for sensitive detection of glucose with a linear range of 0.1

~ 2 mM [24]. After that, FeTCPP-modified porous carbon derived from ZIF-8 and AgNPs@Zn-MOF

modified with glucose oxidase were employed to construct sensitive electrochemical biosensors for

glucose [25, 26] . However, all the above sensors require the use of glucose oxidase, which is unstable

in detection environments and storage environments. Therefore, non-enzymatic electrocatalytic

oxidation of glucose sensors are developed by researchers based on MOFs and their derivates,

especially Ni- and Cu-MOFs [27-29].

Table 1. Analytical performances of MOFs-modified electrodes for biosensing

Analytes Electrode Materials Linear ranges Detection

limits

Refs.

H2O2

[Cu(adp)(BIB)(H2O)]n 0.1 ~ 2.75 μM 0.068 μM [8]

[Co(pbda)(4,4-bpy)·2H2O]n 0.05 ~ 9.0 mM 3.76 μM [9]

MIL-53-CrIII 25 ~ 500 μM 3.52 μM [10]

AP-Ni-MOF 0.004 ~ 60 mM 0.9 μM [11]

Cu-MOF loaded on macroporous carbon 10 ~ 11600 μM 3.2 μM [12]

Pt NPs@UiO-66 (core−shell heterostructure) 0.005 ~ 14.75 mM 3.06 μM [14]

Cu-TDPAT modified with nanosized electrochemically

reduced graphene oxide 4 ~ 12 000 μM 0.17 μM [15]

mesoZIF-8 encapsulating cytochrome c 0.09 ~ 3.6 mM

Not

reported [16]

MOF-derived Fe2O3 nanoparticle 3 ~ 150 μM

150 to 750 μM 0.17 μM [17]

Nitrite

MOF-525 20 ~ 800 μM 2.1 μM [18]

Pd/NH2-MIL-101(Cr) 5 ~ 150 nM 1.3 nM [19]

Metal ions

MOF-5 [Zn4O(BDC)3] 0.01 ~ 8 μM (Pb2+) 4.9 nM [20]

[H2N(CH3)2]4[Zn3(Hdpa)2]·4DMF 5 pM ~ 0.9 μM (Cu2+) 1 pM [21]

Ni-MOF 500 nM ~ 6 μM (Pb2+) 508 nM [22]

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graphene aerogel@UiO-66-NH2

0.06 ~ 3 μM (Cd2+)

0.01 ~ 4 μM (Pb2+)

0.1 ~ 3.5 μM (Cu2+)

0.005 ~ 3 μM (Hg2+)

0.02 μM

1.5 nM

7 nM

2 nM

[23]

Glucose

Ni/NiO/carbon frame/Ni-MOF 4 ~ 5664 μM 0.8 μM [27]

Ni-MIL-77 nanobelts 1 ~ 500 μM 0.25 μM [28]

AgNPs/ZIF-67 2 ~ 1000 μM 0.66 μM [29]

Cu-MOF 0.002 ~ 1.4 mM

1.4 ~ 4.0 mM 0.6 μM [30]

MOF-Derived Porous Ni

2P/Graphene 0.005 ~ 1.4 mM 0.44 μM [31]

Co-MOF on Ni foam 0.001 ~ 3 mM 1.3 nM [32]

NiCo-MOF nanosheets array 0.001 ~ 8 mM 0.29 μM [33]

Small

organic

molecules

AP

Ferrocene-immobilized in-MOF 0.01 ~ 20 μM 6.4 nM [34]

Cu-MOF modified with electrochemically

reduced graphene 1 ~ 100 μM 0.36 μM [35]

DA

MIL-101 5 ~ 250 μM Not

reported

[36]

Cu-MOF modified with electrochemically

reduced graphene 1 ~ 50 μM 0.21 μM

[35]

C/Al-MIL-53-(OH)2 0.03 ~ 10 μM 8 nM [37]

Mn-MOF@MWCNT 0.01 ~ 500 μM 0.002 μM [38]

ZIF-8@graphene 0.003 ~ 1 mM 1 μM [39]

UA MIL-101 30 ~ 200 μM

Not

reported [36]

Mn-MOF@MWCNT 0.02 ~ 1100 μM 0.005 μM [38]

AA [Cu2(HL)2(μ2-OH)2(H2O)5] H2On 0.25 ~ 1.5 mM

Not

reported [40]

Mn-MOF@MWCNT 0.1 ~ 1150 μM 0.01 μM [38]

H Au-SH-SiO2@Cu-MOF 0.04 ~ 500 μM 0.01 μM [41]

Cys Au-SH-SiO2@Cu-MOF 0.02 ~ 300 μM 0.008 μM [42]

HQ Cu-MOF-199@SWCNT

0.1 ~ 1453 μM

0.1 ~ 1150 μM

0.08 μM

0.1 μM

[43]

DHA Cu3(BTC)2 0.04 ~ 1 μM 9 nM [44]

HA AuNPs/MMPF-6(Fe)

0.01 ~ 1 μM and 1 ~ 20

μM 0.004 μM

[45]

urea Ni-MOF@MWCNT 0.01 ~ 1,12 mM 2.5 μM [46]

ATP Cu-MOF@ electroreduced graphene oxide 0.2 ~ 10 μM 0.1 μM [47]

BPA CTAB/Ce-MOF 0.005 ~ 50 μM 2 nM [48]

GA MoxC@C derived from

polyoxometalates@Cu-MOF

0.03 ~ 122 μM

0.02 ~ 122 μM

8.5 nM

8.0 nM

[49]

Abbreviations: BIB: 1,4-bisimidazolebenzene; adp: adipic acid; 4,4-bpy: 4,4-bipyridine; pbda: 3-

(pyridine-3-yloxy)benzene-1,2-dicarboxylic acid; AP: adipic acid; TDPAT: 2,4,6-tris(3,5-

dicarboxylphenylamino)-1,3,5-triazine; DMF: dimethylformamide; Hdpa: 3,4-di(3,5-

dicarboxyphenyl)phthalic acid; MWCNT: multi-walled carbon nanotubes; H2L: 2,5-dicarboxylic acid-

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3,4-ethylene dioxythiophene; SWCNT: single-walled carbon nanotubes; H3BTC: 1,3,5-

benzenetricarboxylic acid; CTAB: hexadecyl trimethyl ammonium bromide.

Small organic molecules can be directly detected by electrochemical methods based on the

electrochemical oxidation or reduction. However, they often suffer from weak anti-interference ability,

poor sensitivity and selectivity due to the low electrocatalytic activity and capacity. This can be

resolved by using MOFs as electrocatalytic electrochemical materials. In most cases, MOFs can not

only provide a lot of electroactive sites to lower the energy barrier for oxidation or reduction, but also

can promote the electron/proton transfer between molecules and the electrode. Besides, MOFs can

adsorb organic molecules through strong π-π, charge donor–acceptor and electrostatic interactions

between molecules and organic linkers. The analytical performances of MOFs-modified electrodes for

the detection of small organic molecules have also presented in Table 1, including acetaminophen (AP),

dopamine (DA), uric acid (UA), ascorbic acid (A)A, hydrazine (H), cysteine (Cys), hydroquinone

catechol (HQ), 2,4-dichlorophenol hydroxylamine (DHA), 2,4,6-trinitrophenol (ATP), bisphenol A

(BPA), and guanine adenine (GA).

3. MOFS AS THE ELECTROCHEMCIAL SIGNAL LABELS

Due to large surface area and manipulatable structural properties, MOF is a promising type of

signal probe for constructing electrochemical biosensors. For example, MOFs with electrocatalytic

ability toward redox substrates as well as electroactive properties from redox-active ligands or metal

nodes and MOFs loading with electroactive molecules or ions have been extensively used to design

electrochemical biosensing methods. Besides, biomolecules can be modified on the surface of MOFs

to regulate the access of redox molecules in solution to the surface of electrodes as gate, which can be

sensitively monitored by electrochemical impedance spectroscopy.

2.1 MOFs as electrocatalysts

As the active center of natural enzymes, porphyrins and its derivates have been widely applied

as mimetic molecules to catalyze organic reactions, such as olefin epoxidation and epoxidation of

hydrocarbons [50-52]. Recently, porphyrin-based MOFs are reported to possess peroxidase-like

catalytic activity and employed to develop fluorescence, colorimetric and electrochemical biosensors

[53, 54]. Lei’s group reported the “signal-on” electrochemical detection of DNA using a prototypal

MOF of HKUST-1(Cu) encapsulated with one-pot synthesized iron(III) meso-5,10,15,20-tetrakis(4-

carboxyphenyl) porphyrin chloride (FeTCPP) as mimetic catalysts (Figure 1A) [55]. The addition of

target DNA triggered the allosteric switch of hairpin DNA to activate SA aptamer. Then, the specific

recognition between SA and its aptamer can introduced FeTCPP@MOF-SA probe to the electrode

surface. The nanoprobe can significantly catalyze the oxidation of o-phenylenediamine (o-PD) to 2,2’-

diaminoazobenzene in the presence of H2O2 and generate a typical electrochemical signal. This

elaborate sensor had a wide linear range of 10 fM to 10 nM with a detection limit lower to 0.48 fM.

Lei and co-workers further designed a nanoscaled porphyrinic MOF (PorMOF) for electrochemical

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detection of telomerase activity, in which iron porphyrin and zirconium ion were used as the linker and

the node, respectively (Figure 1B) [56]. Once telomerase triggered the extension of the assistant DNA

1 (aDNA1) in duplex in the presence of dNTP mixture, the assistant DNA 2 (aDNA2) was liberated

and subsequently hybridized with the capture DNA (cDNA), and the streptavidin (SA) conjugated

PorMOF was introduced to the electrode surface with the biotin-streptavidin biorecognition, resulting

in an increased current of electrocatalytic O2 reduction. The designed sensor exhibited high stability in

broad conditions and even could detect the telomerase activity in a single HeLa cancer cell (2.2 × 10−11

IU). They also applied another type of PorMOFs (PCN-222) as signal nanoprobes for sensitive

detection of DNA with the aid of triple-helix molecular switch and DNA recycling amplification of

Exonuclease III [57]. Moreover, Ju’s group prepared iron-porphyrinic metal-organic framework ((Fe-

P)n-MOF) without other metal ions and modified with Au nanoparticles (AuNPs) to anchor DNAzyme,

GR-5 (Figure 1C) [58]. Under the addition of Pb2+, GR-5 could be specifically cleaved at the

ribonucleotide (rA) site and the produced (Fe-P)n-MOF-labeled short DNA further hybridized with HP

bound on the surface of screen-printed carbon electrode (SPCE). The peroxidase-like (Fe-P)n-MOF

could catalyze the oxidation of TMB by H2O2, significantly increasing the reduction peak current. This

endows the SPCE-based assay with the potential application for low-cost and on-site Pb2+ detection in

various environments.

According to the previous works, Cu-MOFs can also possess superior catalytic activity towards

various substrates and have be widely used in constructing diverse biosensors for the detection of

interests. Yuan’s group developed a sensitive and accurate electrochemical biosensor for

lipopolysaccharide (LPS), integrating the superior catalytic ability of Cu-MOFs and the quadratic

signal amplification of target protein (Figure 1D) [59]. They prepared Cu-MOFs via a hydrothermal

method and in situ generated AuNPs on the surface of Cu-MOFs to carry hairpin probes 3

(HP3/AuNPs/Cu-MOFs). Upon the addition of LPS, the cycle I was initiated with the aid of phi29 and

a lot of output DNA were produced, which could trigger the N.BstNBI-mediated cyclic hairpin

assembly (cycle II), leading to the broken of ferrocene-labeled hairpin probes 2 (Fc-HP2) and the

production of a large amount of capture probes. When the hybridization of capture probes and

HP3/AuNPs/Cu-MOFs, large amounts of Fc left from the electrode and large amounts of

HP3/AuNPs/Cu-MOFs are brought to the surface. Since Cu-MOFs catalyzed the oxidation of glucose

to gluconolactone for the enzyme-free third signal amplification, the change of Fc number and Cu-

MOFs would lead to the remarkable ratiometric electrochemical response. In view of the merits of the

ratiometric electrochemical assays, this strategy decreased the difference between different patches and

has great potential in other analytes detection in complex samples.

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Figure 1. (A) Synthesis of FeTCPP@MOF-SA composite and electrochemical DNA sensing via

allosteric switch of hairpin DNA. Reprinted with permission from [55]. Copyright 2015

American Chemical Society. (B) Schematic illustration of the preparation of nanoscaled

PorMOF and the electrochemical detection strategy for telomerase activity via a telomerase

triggered conformation switch. Reprinted with permission from [56]. Copyright 2016 American

Chemical Society. (C) Schematic representation of preparation of GR-5/(Fe-P)n-MOF probe

and electrochemical detection of Pb2+. Reprinted with permission from [58]. Copyright 2015

American Chemical Society. (D) Schematic illustration of the fabrication of the aptasensor:

preparation procedure of HP3/AuNPs/Cu-MOFs and signal amplification strategy and the

detection principle for LPS. Reprinted with permission from [59]. Copyright 2015 American

Chemical Society.

Other MOFs, containing metal ions with mixed valence state or multiple valence state, can also

possess enzyme-like catalytic ability, and have been used in colorimetric and electrochemical

detection. Chen’s group has reported that three distinct structures of Co/Fe-based MOFs and mixed

valence state Ce(III, IV)-MOF have intrinsic catalytic activities towards the electrochemical reduction

of thionine (Thi, a dye molecule) without any substrates (i.e. H2O2). The MOFs have been applied to

sensitively detect thrombin and ochratoxin A [60, 61]. Besides, MOFs with redox-active ligands can

also be used as electroactive nanoprobes without the addition of any redox mediators. Based on this

principle, Chen’s group designed an electroactive MOF (Ni-MOF) with 4,4’,4’’-

tricarboxytriphenylamine as the electroactive source and Ni4O4 cluster as the node. The resulting Ni-

MOF was applied for electrochemical aptasensing of thrombin [62].

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Moreover, noble-metal NPs or alloy NPs not only can be absorbed on the surface of MOFs to

anchor recognition unites and enhance electric conductivity, but also can be employed as nanozymes

with fascinating catalytic activities [63]. Yuan’s group decorated electroactive Co-based MOFs with

HRP-like PtPd NPs and DNA HP3 as a redox mediator (Co-MOFs/PtPdNPs/HP3). The MOFs were

used for the detection of thrombin (TB) based on the strategy of target-triggering nicking enzyme

signaling amplification (NESA) with the aid of nicking endonuclease (Nt.AlwI) (Figure 2A) [64].

Unlike traditional NESA strategy, in this work, all the produced DNA fragments from the repeated

cycles of hybridization-cleavage initiated by the recognition between TB and the corresponding

aptamer could unfold the DNA HP2 to bring Co-MOFs/PtPdNPs/HP3 close to the surface of the

electrode. In the presence of H2O2, PtPd NPs catalyzed the oxidation of H2O2 and promoted the

conversion of Co2+ to Co3+, further leading to the improvement of the characteristic electrochemical

signal. This aptasensor showed good selectivity, stability and high sensitivity from 1 pM to 30 nM.

The group also prepared hemin-encapsulated Fe-MOFs/PtNPs composites via a one-pot reduction. The

electrocatalytic nanoprobes have the synergistic catalytic activity toward H2O2 by hemin and PtNPs,

and have been used to electrochemical detection of cell-free fetal DNA (cffDNA) [65]. Recently,

electrocatalytic MOFs were combined with DNA-walker-induced conformation switch for

ultrasensitive detection of target DNA (Figure 2B) [66]. First, porphyrinic MOFs (PCN-224) were

modified with palladium nanoparticles (Pd NPs) via in situ reduction and then conjugated with SA as a

recognition element (Pd/PCN-224-SA).

Figure 2. (A) Schematic illustration of the preparation of the preparation of Co-

MOFs/PtPdNPs/HP3and the detection principle for TB. Reprinted with permission from [64].

Copyright 2017 American Chemical Society. (B) Schematic illustration of the synthesis of

Pd/PCN-224-SA tags and the tandem signal amplification strategy based on DNA-walker-

induced allosteric switch and electrocatalysis of Pd/PCN-224-SA in electrochemical

biosensing. Reprinted with permission from [66]. Copyright 2018 American Chemical Society.

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Figure 3. Schematic illustration of the process of the fabrication of the aptamer/HRP/ AuNPs/UiO-66-

NH2 nanoprobes and the electrochemical aptasensor. Reprinted with permission from [67].

Copyright 2018 Springer Nature.

Then, they immobilized the DNA walker substrate on the surface of the indium tin oxide (ITO)

electrode, consisting of a SA aptamer sequence as the track and blocked swing arm as the walker

strand. The added target DNA can hybridize with the blocker through a strand-displacement reaction,

leading to swing arms away from the blocker. Thus, the autonomous moving of DNA walkers was

activated and further powered by the nicking endonuclease (Nb·BbvCI)-catalyzed cleavage of hairpin

DNA. The produced DNA changed to SA aptamer and brought Pd/PCN-224-SA to the electrode

surface via the SA-aptamer recognition, resulting in the enhanced electrochemical signal. This DNA

walker-based system has the advantages of a wide detection linear range, low LOD and single-base

mismatch discrimination ability.

Due to the tunable chemical functionality and porous structures, MOFs have been used to load

drug, protein, and enzyme for the biomedical applications [68-70]. For example, horseradish

peroxidase (HRP) can catalyze the oxidation of substrates by H2O2, and has been encapsulated into

MOFs as electrocatalysts. Chen’s group prepared two aptamers-conjugated Zr(IV)-based MOF (UiO-

66-NH2) to carry HRP for the detection of the Mycobacterium tuberculosis antigen MPT64 (Figure 3)

[67]. In the assay, the surface of MOF was decorated with AuNPs by a one-step hydrothermal

synthesis. The surface of gold electrode and AuNPs/MOF both were labeled with two aptamers with

synergistic effect on binding MPT64. This assay showed a wide linear range from 0.02 to 10000 pg

mL-1 and a lower detection limit (10 pg mL-1). Ai’s group used zeolitic imidazolate framework to load

secondary antibodies (Ab2) and HRP for signal amplification detection of avian leukosis virus

subgroup J [71].

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2.2 Carriers for metal ions

According to previous reports, metal ions, including Cd2+, Pb2+, Cu2+ and Zn2+, exhibit typical

voltammetric characteristics at different applied potentials and have been employed as electroactive

indicators for electrochemical bioassays of metal ions or other molecules [72-82]. For example, Li’s

group utilized Cu2+ ions as the signal-generation indicators to construct a direct electrochemical

method for ultra-trace Cu2+ [73]. Normally, to provide high electrochemical signals, metal ions should

be doped into NPs via ions exchange or be encapsulated into the dendrimer as signal unit [83-85].

However, the modification processes were sometimes time-consuming.

Because of the special pore structure, high surface area, large amounts of metal ions as the

nodes and abundant functional groups in sidewalls, MOFs have also been employed to carry different

electroactive metal ions to develop electrochemical biosensors. For instance, Chen and co-workers

employed UiO-66-NH2 as substrate to carry different metal ions (Cd2+ and Pb2+) for simultaneous

detection of multiple antibiotics based on the specific biorecognition between the corresponding

aptamers and antibiotics [86]. Recently, Zhao’s group also utilized the same strategy for simultaneous

electrochemical immunosensing of triazophos (TRS) and thiacloprid (THD), displacing DNA with

antigen and antibody (Figure 4) [87]. In this study, UiO-66-NH2 was used to adsorb large amounts of

Cd(II) and Pb(II) ions with amino functional groups on the surface, in which the adsorption capacities

were 230 and 271 mg·g−1, respectively. Next, ions-loaded UiO-66-NH2 were labeled with TRS or

THD Ag as the signal tags and carboxyl functionalized magnetic bead (MB-COOH) were coupled with

TRS or THD Ab as the capture probes. In the presence of TRS and THD, the matching MOFs are

specifically replaced and released into the supernatant. After magnetic separation, the dual peak

currents of Cd2+ and Pb2+ in the supernatant are observed simultaneously in one cycle of SWV.

Figure 4. Schematic presentation of an amino-modified metal-organic framework (type UiO-66-NH2)

loaded with Cd(II) and Pb(II) ions for simultaneous electrochemical immunosensing of

triazophos (TRS) and thiacloprid (THD).. Reprinted with permission from [87]. Copyright

2019 Springer-Verlag.

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Unlike traditional signal probes adsorbing additional electroactive metal ions on the surface of

MOFs, Yang’s group first demonstrated that Cu2+-based MOFs (HKUST-1) alone were directly used

as electrochemical signal probes, and Cu2+ in HKUST-1 was directly detected by differential pulse

voltammetric (DPV) scan (Figure 5A) [88]. This circumvents the limitation of acid dissolution and

preconcentration. To rule out the possibility of electrochemical signal derived from free ions adsorbed

on MOFs, the authors conducted a series of experiments and characterization. Furthermore, covalent

organic frameworks (COFs) modified with Pt NPs as the substrate to immobilize capture antibodies

and improve the electronic conductivity. After the formation of the immunocomplex, a high

electrochemical signal could be detected due to large amounts of Cu2+ in HKUST-1. Under the

optimized paraments, this electrochemical immunoassay showed an excellent analytical performance

for C-reactive protein (CRP) detection and had a linear dynamic ranging from 1 to 400 ng/mL with a

detection limit of 0.2 ng/mL. Moreover, they found that other metal ion-contained MOFs (such as

Cd2+- or Zn2+- based MOFs) can also be employed as electroactive signal probes for bioanalysis. In

contrast, Ma’s group successfully prepared two aminated MOFs (Pb-BDC-NH2 and Cd-BDC-NH2)

from Pb(II) or Cd(II) and 2-aminoterephthalic acid (BDC-NH2) and decorated them with two different

antibody toward carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) for immunosensoring

(Figure 5B) [89]. After the formation of immunocomplex in 48-well plate, the bound MOFs were

dissolved by nitric acid. Two liberated metal ions could be easily detected at voltages of −0.63 and

−0.88 V by polyaniline (PANI) nanofibers modified glassy carbon electrode (GCE), respectively. The

presence of PANI improved the electronic conductivity of electrode and the chemical polymerization

method enhanced the accuracy and reproducibility of results.

Figure 5. (A) Schematic illustration of the electrochemical immunosensor for CRP based on Cu-

MOFs. Reprinted with permission from [88]. Copyright 2016 American Chemical Society. (B)

Schematic illustration of the stepwise immunoanalysis process for CEA and AFP based on two

MOFs. Reprinted with permission from [89]. Copyright 2017 Springer-Verlag.

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2.4 Small molecules

Functional biomolecules (e.g. DNA, aptamer, antibody and enzyme) can specifically react with

target molecules, and thus have been widely utilized in developing biosensors, including fluorescence,

colorimetric, electrochemiluminescence and electrochemical biosensors [90-92]. In MOFs-based

electrochemical biosensors, MOFs with pendent functional groups (such as -NH2 and -COOH) can

couple with those biomolecules. Sometimes, organic ligands in MOFs usually having -electron

systems and special functional groups can strongly adsorb single-stranded DNA (ssDNA) in the

interior and on the surface of porous MOFs through π–π stacking, hydrogen-bonding, and electrostatic

interactions. Meanwhile, Zr-based MOFs can also possess high affinity toward biomolecules

containing phosphate groups through the covalent bonds between Zr ion and phosphate radical [93,

94].

Figure 6. Schematic diagram of the AgNCs@Apt@UiO-66-based aptasensor for detecting CEA.

Reprinted with permission from [99]. Copyright 2017 American Chemical Society.

In an electrochemical aptasensor, the adsorption of aptamer and the target-induced change of

the structure or configuration of DNA will subsequently have a significant influence on the electron

transfer between the electrode and the electrolyte solution, which is always evaluated by

electrochemical impedance spectroscopy. Based on this strategy, a few of MOFs and their derivates

have been employed to develop non-label aptasensors for the detection of various molecules, including

antibiotics [95], drug [96], heavy metal ions ( Pb2+ and As3+) [97] and proteins [98-100]. For instance,

Du’s group successfully synthesized three Zr-MOFs with different terminal ligands in channels and

employed them to anchor aptamer strands for constructing electrochemical aptasensor for lysozyme

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detection [98]. At the same time, Zhang’s group also reported a bifunctional electrochemical and

surface plasmon resonance (SPR) aptasensor for carcinoembryonic antigen (CEA) based on Zr-MOF

(UiO-66) and CEA aptamer (Figure 6) [99]. In this work, CEA aptamer was used as the template to

synthesize silver nanoclusters (AgNCs@Apt). The composite AgNCs@Apt @UiO-66 showed active

electrochemical performance and high affinity toward CEA. When CEA was added, CEA aptamer can

specifically bind with CEA, further resulting in the hinderance of redox probe to the surface of

modified AE and the increase of Rct. The proposed method has a wide linear range from 0.02 to 10

ng·mL-1 with a detection limit of 4.39 pg·mL-1. Furthermore, the SPR aptasensor exhibits a higher

detection limit of 0.3 ng·mL−1 within the CEA concentration of 1.0 ~ 250 ng·mL−1. Gold nanoclusters

(AuNCs) were also embedded into Zr-MOF (MOF-521) in Zhang’s group via a one-pot method [96].

The MOFs was applied to construct electrochemical aptasensor for the detection of cocaine. To

improve the loading capacity of aptamers, they successfully encapsulated three kinds of aptamer

strands into Zr-MOF (MOF-509) for detection of thrombin, kanamycin, and CEA [100].

Figure 7. (I) Schematic representation of nucleic acid-functionalized MOFs fabrication procedure and

(II) the principle of the MOF-based homogeneous electrochemical biosensor for multiple

detection of miRNAs. Reprinted with permission from [101]. Copyright 2019 American

Chemical Society.

Besides, due to the porous nanostructure, MOFs can also load electroactive dyes as

nanocontainer with dsDNA as a gatekeeper to cap MOFs, which is released under certain stimulation.

Li’s group used dsDNA-capped UIO-66-NH2 to load two electroactive dyes for ultrasensitive and

simultaneous detection of let-7a and miRNA-21 (Figure 7) [101]. In this work, UIO-66-NH2 was first

prepared and linked with the carboxylated ssDNA CX through the amidation reaction. Next, 3,3’,5,5’-

tetramethyl-benzidine (TMB) and methylene blue (MB) were entrapped into the pores of UIO-66-NH2,

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respectively. Then, another ssDNA PX was used to partially hybridize with CX and cap MOFs, which

was completely complementary to the target biomarker. In the absence of target analytes, the dsDNA

prevented the release of MB and TMB from MOFs, and no significant signal was detected. When

target analytes were added, it was hybridized with PX through the toehold-mediated strand-

displacement reaction and moved away from MOFs, leading to the release of the corresponding

entrapped dyes. The released MB and TMB produced two strong and typical peak currents.

Like the aforementioned aptasensors, in MOFs-based electrochemical immunosensor, the

antibody-antigen interactions can result in an increase of the real component of impedance. In 2015,

Deep’s group reported an immunoassay for impedimetric sensing of parathion based on Cd-MOF and

anti-parathion antibody [102]. Nanocomposites modified with redox species can be labeled with

antibody for designing of amperometric immunosensors. For example, Yu’s group synthesized a novel

redox-active nanocomposite, AuPt-Methylene blue (MB) (AuPt-MB) [103]. The nanocomposite was

applied to develop an amperometric biosensor for the determination of Galectin-3 (Gal-3).

In enzyme-based sensors, the immobilized enzyme can hydrolyze substrates into electroactive

substances that can be oxidized or reduced on the surface of the electrocatalytic MOFs-modified

electrode. Glucose oxidase (GOD) was immobilized on the surface of grapheme-metal coordination

polymer composite nanosheet for the detection of glucose [104]. Chen and co-workers developed an

efficient biosensing platform for bisphenol A (BPA) based on Cu-MOF and tyrosinase, in which Cu-

MOF absorbed BPA through π–π stacking interactions and increased the available BPA concentration

to react with tyrosinase [105]. Recently, Dong’s group synthesized La-MOF-templated wool-ball-like

carbon nanocomposites to immobilize acetylcholinesterase (AChE) for developing the enzyme

biosensor for the detection of methyl parathion (Figure 8) [106]. In this work, three Fe3+, Zr4+, and

La3+-based MOFs were prepared with 2-aminoterephthalate (H2ATA), and further were annealed at

550 °C under N2 atmosphere. The MOFs-derived carbon materials not only possessed more active sites

to immobilize AChE but also facilitated the electron transfer. AChE could hydrolyze into acetic acid

and electroactive thiocholine (TCh), which was further electro-oxidized with the catalysis of the

carbon nanocomposites on the surface of the electrode, generating irreversible oxidation peaks. Methyl

parathion, a kind of pesticide, inhibited the catalytic activity of AChE and could be sensitively detected

with a wide range and low detection limit.

Figure 8. Schematic illustration of the fabrication processes of [M-MOF-NH2]N2 and detection of

methyl parathion. Reprinted with permission from [106]. Copyright 2018 American Chemical

Society.

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5301

4. CONCLUSION

As crystalline molecular materials, MOFs have many advantages over other nanomaterials,

including chemical stability, tunable structure and property, and ultrahigh porosity. Significant

progress has been achieved in the design of novel and excellent MOFs-based electrochemical sensors

and biosensors in the past decade. However, further studies are still desired to address the

shortcomings of MOFs, such as controllable synthesis in nanoscale dimension, higher conductivity and

catalytic activity. With the achievements of nanoscience, MOFs-based electrochemical biosensors

show very promising applications and the electrochemical-related researches will experience

flourishing growth in the next few years.

ACKOWLEDGMENTS

Partial support of this work by the Anyang Normal University Program AYNUKP-2018-B20 and

AYNUKP-2017-B16 was acknowledged.

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